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Objective To evaluate factors impacting survival outcomes in patients with uterine serous carcinoma (USC). Methods Data of consecutive patients diagnosed with USC undergoing surgery between 2000 and 2020 at Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy) were reviewed. Progression-free (PFS) and overall survival (OS) outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models. Results Records of 147 consecutive patients meeting the inclusion criteria were analyzed. Stage distribution was: 67 (45.6%) patients with early-stage with uterine confined disease and 80 (54.4%) with advanced stages disease. Minimally invasive surgery was performed in 43 patients (29.5%). The median follow-up period was 78.6 months (IQ range = 35.7–117.3 months). The overall recurrence rate was 41% (60 patients): 19/67 patients (28.4%) with early-stage disease and 41/80 patients (51.3%) with advanced stage. The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5–44.7%). In multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absent significantly impacted on PFS. The 5-year OS rates were 46.5% (95% CI: 38.1–56.8). The result of multivariate analysis showed that there was significant difference in OS based only on optimal cytoreduction and accuracy of retroperitoneal surgery. Conclusions In apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify patients with disease harboring outside the uterus. Optimal cytoreduction is the most significant prognostic factor. Further collaborative studies are warranted in order to improve outcomes of USC patients.

Background The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. Methods From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method. Results All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. Conclusions The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.

Background This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers. Materials and Methods Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method. Results Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9–13.4) and 21.2 (IQR: 7.7–40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9–61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the “other-regimens group,” responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine. Conclusion Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules. Implications for Practice Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.

Introduction This case-series is aimed to describe the natural history of epithelioid sarcoma (ES) and to provide insights into the differential clinical behaviour of its two variants (“classic-type” and “proximal-type”). The value of a subtype-adapted grading system based on pathological features is explored. Methods Data from consecutive, primary, localised, INI1-deleted ES operated at three Italian sarcoma reference centres (1995–2015) were included. Centralised pathological review was performed. Classic-type ES was broken down into “high-grade” and “low-grade”, according to number of mitoses, evidence of necrosis and nuclear atypia. Five- and 10-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastasis (DM) were estimated. Results Fifty-two patients were included. 5- and 10-year OS estimates were 70% and 47% in the whole series, 57% and 37% in patients with proximal-type ES, 77% and 54% in patients with classic-type ES (P = 0.02). In classic-type ES, 5- and 10-year OS was higher for low-grade (95% and 72%, respectively) than high-grade tumours (P = 0.002). 5- and 10-year CCI estimates for LR were 21% and 33% in the whole series. 5- and 10-year CCI estimates for DM were 35% and 39% in the whole series, both 28% in classic-type ES, 47% and 59% in proximal-type ES (P = 0.03). Conclusions Suffering from a proximal- or a classic-type is the stronger predictor of outcome in patients with localised ES, with proximal-type ES patients having lower survival due to a higher tendency toward metastatic spreading. However, the “high-grade” classic-type ES was associated with outcomes close to proximal-type ES.

The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need.Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-HN35]), progression-free survival and overall survival, duration of response, and toxicities.Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively.Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic urothelial carcinoma.We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed.Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78-1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied.Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.

[Background] This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions., [Methods] Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method., [Results] Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported., [Conclusion] Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.

Purpose: The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor—positive (HR+), HER2-negative (HER2−), advanced breast cancer (HR+/HER2− aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. Experimental Design: We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2− aBC treated with everolimus-exemestane. Results: We evaluated 809 patients with HR+/HER2− aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15–2.69; P = 0.008). Conclusions: The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2− aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2− aBC.

Contains fulltext : 220839.pdf (Publisher’s version ) (Closed access) BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

Aim During the last years, the role of sentinel lymph node mapping (SLNM) for endometrial cancer (EC) surgical treatment has increased in popularity. However, several controversies remain about different technical steps of SLNM. Thus, a randomised control trial was designed to compare cervical (CI) and hysteroscopic (HI) indocyanine green (ICG) injection for SLNM of newly diagnosed EC undergoing surgical staging. The primary end-point of the study was to compare these two techniques in terms of para-aortic detection rate. Methods Patients with apparent stage I or II histologically confirmed EC undergoing surgery were included in the study. This randomised trial distinguished patients in two study groups according to two different techniques of ICG SLNM: CI versus HI injection. Patients who met the inclusion criteria were randomly assigned to CI or HI injection in a 1:1 ratio. The central randomisation system allocated patient randomisation numbers sequentially in the order in which the patients were enrolled. This randomised trial was not blinded for either patients or the surgeons. Results From March 2017 until April 2019, a total of 165 patients were randomised in this study: 85 (51.5%) in the CI group and 80 (48.5%) in the HI group. After randomisation, 14 (8.5%) patients were excluded from the study. Finally, 151 patients were included in the analysis: 82 (54.3%) in the CI group and 69 (45.7%) in the HI group. Hysteroscopy injection shows an ability to detect Sentinel nodes (SNLs) in the para-aortic area of about 10% greater compared with CI injection, although this difference did not reach statistical significance. The HI technique was superior in detecting isolated para-aortic SLNs (5.8% Versus 0%). The CI injection was correlated with higher SLN detection rates at the pelvic level compared with HI injection. Pelvic and overall detection was higher in the CI group. Conclusions The present study supports the adoption of CI instead of HI injection because the former allows better identification of sentinel nodes (especially in the pelvic area). Detection of SLN in the para-aortic area was slightly higher in patients receiving a HI injection, but the difference with the CI route was not statistically significant.

Background Distant metastases in adenoid cystic carcinoma (ACC) are common. There is no consensus on the management of metastatic disease because no therapeutic approach has demonstrated improvement in overall survival (OS) and because of prolonged life expectancy. The aim of this study is to build and validate a prognostic nomogram for metastatic ACC patients. Methods The study end-point was OS, measured from the date of first metastatic presentation to death/last follow-up. A retrospective analysis including metastatic ACC patients was performed to build the prognostic nomogram at the INT (Milan, Italy). The model was validated on an independent cohort of patients with similar characteristics treated at Leuven (Belgium). Outcome data and covariates were modelled by resorting to a random forest method. This machine-learning approach was used to guide and benchmark the subsequent use of more conventional modelling methods. Cox model performance was assessed in terms of discrimination (Harrell's c-index). Results Two hundred ninety-eight patients with metastatic ACC (testing set 259 INT, validation set 39 Leuven) were studied. Akaike Information Criterion–based backward selection yielded a 5-factor model showing a bias-corrected c-index of 0.730. Five independent prognostic factors were found: gender, disease-free interval and presence of lung, liver or bone metastases. Nomogram discrimination in the validation series was c = 0.701. Conclusion This retrospective analysis allowed the building of an externally validated prognostic nomogram. This tool might help clinicians to discriminate patients requiring prompt management from who can benefit from a ‘watchful waiting’. In addition, the nomogram might be useful to stratify patients in clinical trials.

TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III-IV tumors, de-escalate therapy for stage I-II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review.TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease.We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5-year event-free survival and overall survival rates were 89.1% (95% CI 83.6-94.9) and 97.0% (93.7-100) for stage I; 85.1% (79.6-91.1) and 94.0% (90.1-98.1) for stage II (160); 82.7% (75.3-90.8) and 90.9% (85.0-97.1) for stage III (101); and 72.1% (61.9-84.0) and 82.5% (73.1-93.1) for stage IV (69), respectively. On multivariable analysis only anaplasia was significant for event-free survival (HR 2.68, 95% CI 1.48-4.86, p=0.001; bias corrected c-index 0.580) and overall survival (HR 5.29, 95% CI 2.52-11.12, p0.001; bias corrected c-index 0.697).The survival rates achieved and the proposed risk stratification schema provide a basis for future comparisons of Wilms tumor treatment burden and patient outcome.

11558 Background: R showed antitumor activity in a PDX model of dedifferentiated SFT (D-SFT), inducing a superior tumour growth inhibition than with other antiangiogenic agents (A), such as pazopanib (P) and axitinib (A). The efficacy of P and A in patients (pts) with advanced typical- (T-)/ malignant- (M-)SFT has been already confirmed in phase 2 clinical trials, but not in D-SFT. An exploratory phase 2 study was designed to investigate the activity of R in advanced SFT. Methods: An investigator-initiated exploratory phase 2 trial was started in December 2015 at the Istituto Nazionale Tumori, Milan, Italy, to evaluate the activity of R, 160 mg OD, 3 weeks on/1 week off, until progression or limiting toxicity. in > 18 years old pts with advanced SFT. The target sample size was 16 evaluable pts; at least 3 responses were requested to reject the null hypothesis of 5% in favour of an alternative hypothesis of 30% (with type-I and type-II error rates fixed at the 10% level). Eligible pts had to have evidence of progression. Prior treatment with A was allowed. Centralized pathologic review was performed, distinguishing T-SFT, M-SFT and D-SFT subtypes. The primary end-point was the overall response rate (ORR) by Choi. Secondary end-points were ORR by RECIST, progression-free survival (PFS), overall survival (OS). Results: Enrolment was completed in February 2021. Eighteen pts were enrolled (D-SFT = 4; M-SFT = 13; T-SFT = 1). Four pts were naïve, 14 were pre-treated [12 with antiangiogenics (4 with > 1 prior antiangiogenic line); 11 with cytotoxic agents]. Three pts are ongoing, 13 completed their treatment (11 = progression, 1 = toxicity, 1 = other). Fourteen pts are evaluable for response by Choi and RECIST (1 = screening failure; 1 = early discontinuation for toxicity before radiologic assessment; 2 = too early). A definitive dose reduction was required in 5 of 14 evaluable (35.7%) pts. The ORR by Choi was 42.9% (exact binomial 95% Confidence Interval [CI]: 17.7%-71.1%), with 6/14 (42.9%) partial responses (PR), 5/14 (35.7%) stable disease (SD) and 3/14 (21.4%) progressions (PD). Best responses by RECIST were: 1/14 (7.1%) PR, 10/14 (71.4%) SD, 3/14 (21.4%) PD. 5/6 pts responsive by Choi were pre-treated with another antiangiogenic. No responses were seen in the 3 D-SFT pts. At a m-FU of 23 months, m-PFS by Choi was 3.68 (IQR: 2.73-8.54) months, with 23.4% pts progression free at 1 year. m-PFS by Choi in responsive pts was 5.62 (IQR: 2.89 – 8.54) mos. Median OS was 15.7 (IQR: 7.35-not reached) months. Conclusions: R did not show a higher activity in D-SFT compared to P and A. The response rate was in the range observed with other A, but m-PFS was shorter. This may be due to discrepancies in pt populations and a high-rate of dose reductions with R. However, responses to R were seen also in pts previously treated with other A and almost one fourth of pts benefited from R for more than a year. Clinical trial information: 2015-002629-21.

11570 Background: In recent years evidence of long term stabilization and spontaneous regression of primary sporadic DT resulted in a paradigm shift towards more conservative approaches. We present herein the results of an observational study aimed at prospectively assess the behavior of primary sporadic DT initially managed by active surveillance and its relation to CTNNB1 mutational status. Methods: This is an Italian prospective, multicenter, observational study (NCT 02547831) to evaluate primary sporadic DT behavior in patients (pts) >16 years with primary naive or incompletely resected and measurable disease, at any site, with CTNNB1 mutational status available. Pts were assessed by contrast enhanced MRI or CT scan at baseline, at 3, 6, 9, 12 months, then every 6 months until the third year. Tumor changes were assessed by RECIST. In case of dimensional or symptomatic progression active treatment could be proposed on an individualized basis CTNNB1 mutational status was obtained in all patients by Sanger and deep sequencing was performed in wild-type cases. Primary end-point was progression-free survival (PFS) at 3 yrs. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated using survival analysis methods, including Kaplan-Meier plots, log-rank test for survival curves comparison, and Cox proportional-hazard multivariable regression (age, size, anatomic site and CTNNB1 mutational status). Results: From April 2013 to February 2018 108 pts were included (82% female, 18% male); median age was 39 (interquartile range, IQR 34-48) and median size 50 mm (IQR, 40-80 mm). Tumor location was: 4/108 (4%) = head&neck, 25/108 (23%) = trunk, 59/108 (55%) = abdominal wall, 3/108 (3%) = intra-abdominal, 17/108 (16%) = extremities. CTNNB1 mutations were as follow: T41A 54/108 (50%), S45F 13/108 (12%), WT 20/108 (19%), other mutations 21/108 (19%). At a m-FU of 32.3 months, the 3-year PFS was 54.5% (95% CI, 44.9%-66.1%). 42/108 (39%) pts showed a RECIST progression, with equal distribution among the different anatomic sites. None of the variables analyzed were associated to PFS. Spontaneous regression was initially observed in 27/108 (25%) patients, while it followed dimensional progression in another 33/108 (30%). 35/108 (32%) pts received active treatment, 18/42 (43%) after RECIST progression and 17/66 (26%) after symptomatic progressions. TFS at 36 months was 65.9% (95% CI, 57.3%-75.9%). S45F mutation, larger tumor size and extremity location were associated to a shorter TFS. No dimensional or symptomatic progression were observed after 36 months of FU. Conclusions: Active surveillance was marked by spontaneous regressions in 60/108 (55%) pts. An active treatment was needed in 32%. If no events occur after 3 yrs of FU, more relaxed FU schedules can be considered given the low risk of subsequent progression. Attention should be paid to patients with DT located to the extremity and/or carrying a S45F mutation. Clinical trial information: NCT 02547831.

Objective: To analyse the outcomes of adjuvant chemotherapy vs observation in a multicentre cohort of patients with upper tract urothelial carcinoma (UTUC) in order to clarify whether such patients benefit from adjuvant chemotherapy after radical nephroureterectomy (RNU). Patients and Methods: Data from 15 centres were collected for a total of 1544 patients, treated between 2000 and 2015. Criteria for patient selection included pT2–4N0/x stage, or lymph node-positive disease, and prior RNU. The standardized difference approach was used to compare subgroup characteristics. Overall survival (OS) was the primary endpoint. The primary analysis used 1:1 propensity score matching, with inverse probability of treatment weighting in addition to this in the secondary analysis. The latter was also performed with the inclusion of covariates, i.e. with ‘doubly robust’ estimation. A 6-month landmark analysis was performed to exclude early events. Results: A total of 312 patients received adjuvant chemotherapy and 1232 underwent observation. Despite differences between the two groups, the standardized difference was generally

In a retrospective analysis of data from 13 European Society for Blood and Marrow Transplantation (EBMT) centers, we evaluated the contemporary outcomes of high-dose chemotherapy (HDCT) as salvage therapy of advanced seminoma. The results supported the use of HDCT, particularly for patients with chemosensitive disease. This proof of concept needs to be prospectively validated in a randomized trial of HDCT versus standard-dose chemotherapy. Background: The optimal management of advanced seminoma that relapses after chemotherapy remains unknown. We retrospectively analyzed outcomes with the use of high-dose chemotherapy (HDCT). Patients and Methods: Eligibility included adult male patients with pure seminomatous histology and treatment with salvage HDCT. Data of patients who received HDCT from 13 European Society for Blood and Marrow Transplantation (EBMT) centers were used. Multivariable Cox analyses evaluated the association of prespecified factors (line of treatment, prior radiotherapy, and chemosensitivity according to standard definition), with progression-free (PFS) and overall survival (OS). The prognostic ability of the model was assessed through the concordance statistic. Results: From December 2002 to December 2012, 46 cases were identified. Median age was 38 years (interquartile range, 35-46 years). HDCT was provided as second-line therapy (n = 14, 30.4%) and in third-line or beyond third-line therapy (n = 20, 43.5%; 12 had missing information). Sixteen patients (34.8%) received paraortic and/or iliac radiotherapy, and 10 (21.7%) had disease that was cisplatin refractory or absolutely refractory. Median follow-up was 22 months (interquartile range, 8-56). On multivariable Cox analysis, refractory disease was a significantly negative prognostic factor for both PFS (hazard ratio, 6.04; 95% confidence interval, 1.86-19.64) and OS (hazard ratio, 3.93; 95% confidence interval, 1.07-14.45), while prior radiotherapy trended to significance for both. The c index was 0.74 and 0.66 for PFS and OS, respectively. The small numbers and the lack of any comparison with conventional-dose chemotherapy are major study limitations. Conclusion: Despite our small sample size, this retrospective analysis suggested that HDCT may represent a valuable therapeutic option for patients with a pure seminoma after standard-dose chemotherapy failure. Our observation requires validation through a prospective study.

The administration of adjuvant chemotherapy for patients with penile squamous cell carcinoma (PSCC) with high-risk features is controversial. In 21 patients who had received adjuvant taxane, cisplatin, and 5-fluorouracil, the expression of p53 in the tumor-positive lymph nodes was the only factor that showed a trend toward poorer survival endpoints. If confirmed, these findings could help in selecting the best candidates for adjuvant chemotherapy. Background: Little is known about the outcomes and prognostic factors of adjuvant chemotherapy for locally advanced penile squamous cell carcinoma after regional lymphadenectomy (LAD). Patients and Methods: We retrospectively reviewed the data from 21 patients who had received taxane, cisplatin, and 5-fluorouracil (TPF, every 3 weeks) in the adjuvant setting at our center. Univariable and multivariable Cox regression analyses were undertaken for disease-free (DFS) and overall survival (OS) of TPF. Results: The patients had received TPF from July 2004 to July 2012 after inguinal (n = 6) or inguinal plus pelvic LAD (n = 15), and the median follow-up was 52 months. Thirteen (61.9%) had pelvic and 5 (23.8%) bilateral inguinal nodal metastases. The median time from LAD to the start of TPF was 5.4 weeks (interquartile range [IQR], 4.1-7.3 weeks). Metastatic tumor tissue from 11 of 19 evaluable patients (57.9%) showed positive immunohistochemistry staining for p53. Univariably, only the expression of p53 showed a trend toward poorer DFS (hazard ratio [HR], 4.14; 95% confidence interval [CI], 0.87-19.68; P = .074) and OS (HR, 4.54; 95% CI, 0.95-21.56; P = .056). The same results were obtained multivariably for DFS (HR, 3.76; 95% CI, 0.78-17.96; P = .096) and OS (HR, 4.29; 95% CI, 0.89-20.57; P = .067). The median DFS was 8.9 months (IQR, 5.9-22.7 months) for p53-expressing patients versus not estimable for non p53-expressing patients (P = .051) and the median OS was 17.2 months (IQR, 12.8-22.7 months) and not estimable, respectively (P = .037). Conclusion: In patients who had received adjuvant TPF for node-positive penile squamous cell carcinoma, p53 IHC expression seemed to be associated with a poorer outcome, and further study is warranted in larger data sets to confirm these findings. This information might be useful to improve the prognostic allocation. (C) 2016 Elsevier Inc. All rights reserved.

Previous works linked low sodium concentration with mortality risk in cancer. We aimed at weighing the prognostic impact of hyponatremia in all consecutive patients with metastatic solid tumors admitted in a two-years period at our medical oncology department. Patients were included in two cohorts based on serum sodium concentration on admission. A total of 1025 patients were included, of whom 279 (27.2%) were found to be hyponatremic. The highest prevalence of hyponatremia was observed in biliary tract (51%), prostate (45%) and small-cell lung cancer (38.9%). With a median follow-up of 26.9 months, median OS was 2 months and 13.2 months for the hyponatremia versus control cohort, respectively (HR, 2.65; P P

OBJECTIVE To evaluate the prognostic impact of lymph node yield (LNY) on survival outcomes for penile squamous cell carcinoma (SCC). PATIENTS AND METHODS In all, 532 patients who underwent inguinal LN dissection (ILND) across tertiary referral centres from Europe, China, Brazil and North America were retrospectively evaluated. From this cohort, 198 patients received pelvic LND (PLND).We identified threshold values for ILND and PLND using receiver operating characteristic curves. We tested prognostic value of LNY for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) using the Kaplan-Meir method and Cox proportional hazard regression models. RESULTS The median (interquartile [IQR]) age was 59 (49-68) years and the median (IQR) follow-up after ILND was 28 (12-68.2) months. Overall, 85% of the patients had bilateral dissections. The median (IQR) number of inguinal LNs removed was 15 (10-22). Of those receiving PLND, The median (IQR) number of LNs was 13 (8-19). A LNY of ≥15 was used for dichotomisation of ILND patients, and a LNY of ≥9 was used in the PLND cohort. Patients with a LNY ≥15 had significantly better 5-year OS vs patients with a LNY

INTRODUCTION AND OBJECTIVES:The main prognostic factors for survival among patients with penile squamous cell carcinoma (PSCC) remain the presence and the extent of lymph node metastasis (LNM). Kno...

Background: Limited data is available on the role, and extent of, postchemotherapy lymphadenectomy (PC-LND) in patients with clinical evidence of pelvic (cN1-3) or retroperitoneal (RP) lymph node spread from urothelial bladder carcinoma. Objective: To compare the outcomes of operated versus nonoperated patients after first-line chemotherapy. Design, setting, and participants: Data from 34 centers was collected, totaling 522 patients, treated between January 2000 and June 2015. Criteria for patient selection were the following: bladder primary tumor, lymph node metastases (pelvic. ±. RP) only, first-line platinum-based chemotherapy given. Intervention: LND (with cystectomy) versus observation after first-line chemotherapy for metastatic urothelial bladder carcinoma. Outcome measures and statistical analysis: Overall survival (OS) was the primary endpoint. Multiple propensity score techniques were adopted, including 1:1 propensity score matching and inverse probability of treatment weighting. Additionally, the inverse probability of treatment weighting analysis was performed with the inclusion of the covariates, that is, with doubly robust estimation. Results and limitations: Overall, 242 (46.4%) patients received PC-LND and 280 (53.6%) observation after chemotherapy. There were 177 (33.9%) and 345 (66.1%) patients with either RP or pelvic LND only, respectively. Doubly robust estimation-adjusted comparison was not significant for improved OS for PC-LND (hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.56-1.31, p = 0.479), confirmed by matched analysis (HR: 0.91, 95% CI: 0.60-1.36, p = 0.628). This was also observed in the RP subgroup (HR: 1.12, 95% CI: 0.68-1.84). The retrospective nature of the data and the heterogeneous patient population were the major limitations. Conclusions: Although there were substantial differences between the two groups, after accounting for major confounders we report a nonsignificant OS difference with PC-LND compared with observation only. These findings may be hypothesis-generating for future prospective trials. Patient summary: We found no differences in survival by adding postchemotherapy lymphadenectomy in patients with pelvic or retroperitoneal lymph node metastatic bladder cancer. The indication to perform postchemotherapy lymphadenectomy in the most suitable patients requires additional studies. In contemporary cohorts of patients with metastatic pelvic or retroperitoneal lymph nodes from bladder cancer, we found no survival benefit from postchemotherapy surgery versus observation in a retrospective study. Performing postchemotherapy lymphadenectomy remains investigational in patients with metastatic bladder cancer.

FGFR gene alterations represent a target for treatment in clinical trials of urothelial carcinoma (UC). Little is known about their prognostic effect in patients with metastatic UC. We analyzed data for 112 patients treated with platinum-based first-line chemotherapy at our center between October 2011 and March 2017 and who were screened for the presence of FGFR mutations or gene fusions within multiple clinical trials with pan-FGFR inhibitors. Centralized targeted exome sequencing analyses were performed to detect multiple FGFR mutations and fusions. Cox regression analyses were performed, adjusting for recognized prognostic factors. Thirty-seven patients (33%) had upper tract UC (UTUC). A total of 22 patients (19.6%) had FGFR alterations and ten (8.9%) received salvage pan-FGFR inhibitor therapy. Thirty-two patients (45.4%) received salvage treatment with an immune checkpoint inhibitor. FGFR alterations were more frequently observed in UTUC versus bladder UC (p=0.017). On multivariable analyses, FGFR alterations were not significantly associated with OS (p=0.860) or PFS (p=0.147) after first-line chemotherapy. PATIENT SUMMARY: In an original single-center study, FGFR gene alterations were not prognostic for either progression-free survival or overall survival in patients receiving first-line chemotherapy for metastatic urothelial carcinoma. These results will be useful in interpreting findings from future clinical trials.

To improve the prognostic allocation of patients with penile squamous-cell carcinoma (PSCC) receiving regional lymph node dissection (LND).An international, multicenter, retrospective study was performed on patients with PSCC who received regional LND, with or without perioperative therapy, from 1980 to 2017. We first used a random forest (RF) method with missing data imputation. Additionally, data were modeled using Cox proportional hazard regression, and a Cox model was also fit including prespecified variables. Based on the latter model, a nomogram for estimating 12-month and 24-month overall survival (OS) was developed.There were 743 patients who received LND at 7 referral centers from Europe, the USA, Brazil, and China. Of these patients, 689 were analyzed: 86 (12.5%) received neoadjuvant chemotherapy (NAC); 171 (24.8%) received adjuvant chemotherapy (AC), and 74 (10.7%) received adjuvant radiotherapy. The variables significantly associated with OS were age (P0.001), the pathologically involved/total removed LN ratio (P0.001), pN stage (overall P0.001), and NAC (P = 0.013). NAC and AC were ineffective in N1-2 patients (clinical and pathological, respectively), whereas they provided OS improvements in N3 patients. Finally, we developed a nomogram predicting 12- and 24-month OS based on prespecified variables (c-index: 0.75). The study is limited by its retrospective nature.We propose a tool that can be offered as an aid to physicians to enhance decision-making, clinical research, and patient counseling whenever LND is needed for PSCC. Administration of NAC and AC should be restricted to clinical and pathological N3 patients, respectively.

11065 Background: To report on a multi-institution retrospective study on the activity of anthracycline-based (Ab) and gemcitabine-based (Gb) regimens as well as pazopanib (P) in patients with advanced epithelioid sarcoma (ES) treated within 16 sarcoma reference centres in Europe, US and Japan. Methods: Patients with a histologically confirmed diagnosis of locally advanced/metastatic ES were selected. Classic and distal subtypes were defined based on morphology (WHO 2014). INI1 expression is under evaluation.Response was evaluated by RECIST.Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Results: Ninety ES patients were identified (Table 1). They were treated with Ab (72), Gb (30) and P (20); 25 pts received more than one treatment. The median follow-up for Ab, Gb and P groups was 32, 24 and 22 months, respectively. The response rate (RR) for Ab was 25% (95% CI 16%-37%), with a median PFS and OS of 6 and 17 months. The RR for Gb was 23% (95% CI 10% - 42%), with 1 complete response and a median PFS and OS of 5 and 20 months. In the P group, no objective responses were reported, and median PFS and OS were 3 and 9 months. A non-statistically significant trend towards a greater RR in proximal than classic subtype was seen in both Ab (27% vs 22%) and Gb (30% vs 13%) groups. Conclusions: This retrospective series, the largest currently available, confirms the activity of Ab and Gb in ES, with a similar RR and PFS in both groups. In this population, the value of P seems limited. These data may serve as a benchmark for trials of novel agents in ES. [Table: see text]

Panitumumab showed clinical activity in patients with penile squamous cell carcinoma from a single center. The targeting of the epidermal growth factor receptor will deserve investigation in combination with chemotherapy and in earlier stages. New insights into the biology of disease and into the current role of standard chemotherapy are required to better select the optimal candidates for treatment. Background: Patients with metastatic penile squamous cell carcinoma (SCC) have a poor prognosis and treatment options are needed when chemotherapy treatment fails. We present the final results of panitumumab treatment from our original series. Patients and Methods: Eligibility included patients with unresectable or metastatic penile SCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and failure of at least 1 chemotherapy regimen. Patients received panitumumab 6.0 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Response was assessed by clinical examination or Response Evaluation Criteria in Solid Tumors version 1.1 criteria every 6 weeks, when applicable. Descriptive statistics were calculated and univariable Cox proportional hazards regression analysis was conducted. Results: Between October 2010 and July 2013, 11 patients were treated. After a median of 5 panitumumab administrations (range, 1-11), we recorded 1 case of Grade 3 cutaneous toxicity and diarrhea each, and 2 cases of Grade 3 mucositis. One patient discontinued treatment because of skin toxicity. Two patients had a complete remission of skin nodules and of skin and nodal metastases, respectively. One patient had a partial regression of skin metastases, and 2 patients stable disease (clinical benefit: 45.5%). Median progression-free survival was 1.9 months (interquartile range [IQR], 0.9-3.0 months) and median overall survival (OS) was 9.5 months (IQR, 4.9-12.6). The presence of visceral metastases showed a trend for association with worse OS (P = .098). Conclusion: Panitumumab was active and safe in patients with highly pretreated penile SCC. The design of combination or sequential strategies with chemotherapy and in an earlier disease stage is warranted. (C) 2015 Elsevier Inc. All rights reserved.

Purpose Obesity is a known risk factor for breast cancer and has been linked to increased risk of recurrence and death in breast cancer patients. Little is known about the predictive value of obesity. As endocrine therapy is widely used for breast cancer treatment worldwide, we aimed at correlating baseline body mass index (BMI) with clinical benefit derived from fulvestrant in postmenopausal women with advanced breast cancer. Methods We analyzed consecutive patients treated with fulvestrant in our center between January 2009 and March 2015. Patients were categorized as normal (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29 kg/m2) and obese (BMI >30 kg/m2). The antitumor activity of fulvestrant was evaluated in terms of the clinical benefit rate (CBR). Results Seventy-five consecutive patients matched the eligibility criteria for analysis. Fulvestrant was administered as first-line therapy in 4 (5%) cases, as second line in 27 (36%) and as third line and beyond in 44 (59%) cases. According to BMI, 44 (59%) patients were classified as normal weight, 19 (25%) as overweight, and 12 (16%) as obese. No difference in estrogen receptor expression was found in relation to BMI. CBR was 53% overall, but rose to 70.5% in normal-weight patients and dropped to 31.6% and 25% in overweight and obese patients, respectively (pConclusions Increased BMI has a negative influence on treatment outcome. Even with the limitation of the relatively small sample size, it appears that patients of normal weight are 2.5-fold more likely to benefit from fulvestrant as overweight and obese patients.

Background The potential impact of diagnostic delays on patients’ outcomes is a debated issue in pediatric oncology and discordant results have been published so far. We attempted to tackle this issue by analyzing a prospective series of 351 consecutive children and adolescents with solid malignancies using innovative statistical tools. Methods To address the nonlinear complexity of the association between symptom interval and overall survival (OS), a regression tree algorithm was constructed with sequential binary splitting rules and used to identify homogeneous patient groups vis-a-vis functional relationship between diagnostic delay and OS. Results Three different groups were identified: group A, with localized disease and good prognosis (5-year OS 85.4%); group B, with locally or regionally advanced, or metastatic disease and intermediate prognosis (5-year OS 72.9%), including neuroblastoma, Wilms tumor, nonrhabdomyosarcoma soft tissue sarcoma, and germ cell tumor; and group C, with locally or regionally advanced, or metastatic disease and poor prognosis (5-year OS 45%), including brain tumors, rhabdomyosarcoma, and bone sarcoma. The functional relationship between symptom interval and mortality risk differed between the three subgroups, there being no association in group A (hazard ratio [HR]: 0.96), a positive linear association in group B (HR: 1.48), and a negative linear association in group C (HR: 0.61). Conclusions Our analysis suggests that at least a subset of patients can benefit from an earlier diagnosis in terms of survival. For others, intrinsic aggressiveness may mask the potential effect of diagnostic delays. Based on these findings, early diagnosis should remain a goal for pediatric cancer patients.

Item does not contain fulltext Importance: Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease. Objective: To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES. Design, Setting, and Participants: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria. Exposures: All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib. Main Outcome and Measures: Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines). Results: Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months. Conclusions and Relevance: This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.

Background We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma. Methods In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response. Results Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively. Conclusions Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

Background In colorectal cancer liver metastases (CRCLM), bevacizumab-based neoadjuvant strategies provide increased pathologic response. We aimed at assessing the activity of perioperative capecitabine, oxaliplatin, irinotecan, and bevacizumab (COI-B regimen) in patients with potentially resectable CRCLM, and investigating biomarkers for early prediction of pathologic response. Patients and Methods This was a single-center phase II study enrolling patients with liver-limited, borderline resectable disease and/or high-risk features. Patients received 5 preoperative and 4 postoperative cycles of biweekly COI-B (irinotecan 180 mg/m2 and bevacizumab 5 mg/Kg on day 1, oxaliplatin 85 mg/m2 on day 2, and capecitabine 1000 mg/m2 twice a day on days 2 to 6). The primary endpoint was pathologic response rate in the intention-to-treat population. A Simon 2-stage design was adopted to detect an increase from 30% to 50% with a power of 90%. Dynamic imaging biomarkers (early tumor shrinkage [ETS], deepness of response, maximum standardized uptake volume [SUVmax]/regression index) and next generation sequencing data were explored as surrogates. Results From June 2013 to March 2017, 46 patients were enrolled. Pathologic response was achieved in 63% patients (endpoint met), and responders achieved significantly better survival outcomes with respect to non-responders. The most frequent grade 3/4 adverse events were diarrhea and neutropenia (8.7%) in the preoperative phase and thromboembolic events (5.9%) in the postoperative phase. ETS and lower SUV-2 were significantly associated with pathologic response. Conclusion The COI-B regimen is a feasible and highly active perioperative strategy in patients with molecularly unselected, potentially resectable CRCLM. ETS and SUV-2 have a promising role as imaging-based biomarkers for pathologic response.

Objective To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor. Patients and Methods In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2-3 or M1 (TNM 2009), and no prior chemotherapy administration. The primary endpoint was the objective response-rate (ORR, according to RECIST v1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. Results From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically-involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR: 32.1%, 80% credibility interval 21.0-43.0%). The median follow-up duration was 19.8 months (IQR: 6.3-25.7); 12-month progression-free survival was 26.2% (95%CI: 13.2-51.9); 12-month overall survival (OS) was 54.9% (95%CI: 36.4-82.8). The median OS of locally-advanced patients was 20 months (IQR: 11.1-not reached). The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in 3 patients (10.7%). Tissue samples from 25 patients were analyzed. Only two patients had HR-HPV-positive tumor. EGFR amplification was found in 4 patients (equally responders and non responders) and it was confirmed in all post-dacomitinib samples. TERT mutations (60%) were found in responders only, PI3K/mTOR pathway gene mutations in 42.9% responders versus 8.3% non responders. Conclusion Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combination chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signaling in relation to dacomitinib activity deserve further studies. This article is protected by copyright. All rights reserved.

Background Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). Patients and methods After transurethral resection of the bladder, T2–T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400 mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively. Results From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9–58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0–69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6–NR), nor was median overall survival (interquartile range: 30.3–NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response ( P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution. Conclusions SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy.

Background Androgen deprivation therapy has some clinical activity in selected salivary gland cancer histotypes, with androgen receptor expression. Methods We retrospectively analyzed patients with androgen receptor-expressing recurrent/metastatic salivary gland cancer, treated with androgen deprivation therapy. Protein expression of androgen receptor and ErbB family members was investigated. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. Results Seventeen patients were identified. No significant toxicities were reported. Overall response rate was 64.7%; 3-year PFS and 5-year OS were 11.8% and 19.3%, respectively. Androgen receptor overexpression may be sustained by gain of chromosome X (58%) and TP53 mutation (44%). No association between response to androgen deprivation therapy and epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, HER3 expression, PIK3CA mutations, or phosphatase and tensin homolog (PTEN) deletion was identified. Conclusion We confirm the activity of androgen deprivation therapy in androgen receptor-expressing recurrent/metastatic salivary gland cancers. The hypothesis that an androgen receptor increased gene copy number may represent a possible mechanism of primary resistance should be further investigated. © 2015 Wiley Periodicals, Inc. Head Neck 38: 724–731, 2016

Background Limited information is available regarding the use of androgen receptor (AR) immunohistochemical expression in muscle-invasive or metastatic urothelial carcinoma. We aimed to evaluate the frequency of AR expression by tumor cells (TC), its prognostic role, and its relationship with programmed cell-death ligand 1 (PD-L1) expression in these patients. Patients and Methods From September 2015 to January 2017, we collected tissue from patients who received platinum-based chemotherapy at our center. Immunohistochemistry for AR was performed (1% cutoff of TC). PD-L1 coexpression, by TC or immune cells (1% cutoff), was also analyzed. Molecular analysis of AR gene was performed by sequencing of exons 5 to 8 and by fluorescence in-situ hybridization analysis. Cox models for overall survival (OS), adjusted for stage, visceral metastases, and platinum type, were fitted. Results A total of 110 patients had tumor samples stained. Overall, 48 (43.6%) had AR-expressing TC: 19 (17.3%) had 1%-5% expression, 15 (13.6%) 5%-25% expression, and 14 (12.7%) > 25% expression. Among the latter, 7 had molecularly evaluated tumor tissue: no AR gene mutations or amplifications were found, but polysomy of Xq chromosome was seen. PD-L1 expression by TC and immunohistochemistry concordantly decreased with increasing levels of AR expression by TC. In Cox analyses, AR expression was not associated with OS, both on univariable ( P = .477) and multivariable ( P = .505) analyses. Conclusion AR is frequently expressed in patients with muscle-invasive and advanced urothelial carcinoma, and it does not seem to be prognostic for OS. The AR pathway is worthy of clinical studies to assess its synergistic action with anti–PD-L1 therapy.

Although large-scale randomised clinical trials have established that radiotherapy (RT) - alone or combined with hormonal therapy (HT) - is effective in reducing the risk of ipsilateral breast tumour recurrence (IBTR), overall survival does not seem to be improved by adjuvant therapies. We sought to ascertain whether specific criteria can be adopted to avoid RT with an acceptable rate of IBTR after breast-conserving surgery (BCS) achieving tumour-free margins.This non-randomised prospective study concerned the outcome of patients who underwent BCS for ductal carcinoma in situ (DCIS) and were prospectively assessed by means of an established scoring system based on width of free margins in association with age40, presence of comedonecrosis, high grade, ER negativity and HER2 positivity, to orient the use of any adjuvant therapies.From March 2000 to April 2006, a total of 224 patients were enrolled and followed up for this study. No adjuvant treatment was considered for 76 patients, while 53, 39 and 56 patients received HT alone, RT alone, and RT plus HT, respectively. After a median follow-up of 129.6 months, 25 patients developed an IBTR, corresponding to a yearly rate of 1.138% (95% CI: 0.769-1.684).When the criteria considered in the present study were applied to address the use of adjuvant therapies, no RT was administered to 57.6% of patients, 33.9% received no adjuvant treatments at all, and the rate of IBTR was low. Our findings support the conviction that the risk/benefit of omitting RT may lean on the side of the latter in selected patients.

Aims The purpose of this observational study was to evaluate disease free survival (DFS), overall survival (OS), and local recurrence rate (LRR) in patients submitted to Class II RH compared with Class III RH in early FIGO stage cervical cancer (ECC). Materials and methods We investigated 127 patients with CC admitted to the National Cancer Institute of Milan from June 2001 to October 2011 treated with Class II RH, and compared them with 202 patients operated with Class III RH between March 1980 and March 2001. A total of 329 patients were collected. Results Median follow-up time was 91 months (IQ range:58–196). Five-year OS and DFS estimates were 89.5% (95%CI: 86.0–93.2%) and 85.6% (95%CI: 81.6–89.7%), respectively. Estimates of effect of surgical treatment (Class III RH versus Class II RH) on OS showed a HR of death = 3.38 (95%CI: 1.18–9.63, P = 0.0228), at univariable Cox analysis, and a HR = 3.08 (95%CI: 0.96–9.93; P = 0.0595) at multivariable analysis. For DFS, a HR of relapse = 2.51 (95%CI 1.10–5.72; P = 0.0290) comparing Class III vs Class II was found at multivariable analysis. Overall recurrence rate was 12.8%, whilst it was 16.3% for Class III and 7.1% for Class II respectively. Conclusions The present data suggest that the outcomes of Class II RH are comparable in terms of LRR and OS to those of Class III RH, according to literature data. The opportunity of extending the indication to all women with ECC needs further investigations. Clearer data are warranted by prospective controlled studies.

512 Background: Advances in prognostic allocation of pts with PSCC receiving regional LND are needed, along with an assessment of the role of perioperative treatments. Methods: An international, multicenter, retrospective database was queried for all pts with PSCC who had received inguinal ± pelvic LND from 1980 to 2017. We classified or re-classified pts according to the 2009 TNM classification system. The primary endpoint was OS. Survival analysis methods were adopted for the purpose of detecting and modeling putative prognostic factors, and develop a prognostic stratification tool. The analysis was performed in two steps: first, we modeled outcome data and covariates by resorting to a random forest (RF) method (an “ensemble” machine-learning approach, with an ad hoc approach incorporating missing data imputation). Second, data was modeled using Cox proportional hazard regression. In addition, a Cox model was fit including pre-specified variables that were deemed to be clinically relevant. Results: There were 743 pts who received LND at seven referral centers from Europe, the USA, Brazil, and China. Of these pts, 689 were analyzed: 86 (12.5%) received neoadjuvant chemotherapy (NAC); 171 (24.8%) received adjuvant chemotherapy (AC), and 74 (10.7%) received adjuvant radiotherapy. The variables significantly associated with OS were age (p < 0.001), the pathologically involved/total removed LN ratio (p < 0.001), pN stage (overall p < 0.001) and NAC (HR: 1.58, 95%CI: 1.10-2.26, p = 0.013). NAC and AC were ineffective or detrimental in N1-2 patients, whereas they provided OS improvements in N3 patients. OS improvement reached statistical significance for AC in pelvic LN-positive pts (p = 0.046). Finally, we developed a nomogram predicting 12- and 24-month OS based on pre-specified variables (c-index: 0.75). The study is limited by its retrospective nature. Conclusions: We propose a post-treatment prognostic tool that can be offered as an aid to physicians to enhance decision-making, clinical research, and patient counseling after LND in PSCC. Administration of NAC and AC should be restricted to N3 patients.

To investigate whether the total number of removed lymph nodes (LNs) and the number of metastatic LNs would prove to be independent prognostic factors for survival in patients with cervical cancer (CC). Data from patients with CC who underwent radical surgery between March 1980 and September 2009 were reviewed. A total of 526 patients were included in the statistical analysis. Full pathologic evaluation was performed. The total number of examined LNs and their histopathological status were analyzed for their prognostic effect on survival by means of multivariable Cox proportional hazard regression models. The median number (interquartile range) of total, pelvic, and para-aortic nodes removed was 37 (29–47), 34 (27–42), and 19 (14–24), respectively. Positive pelvic nodes were found in 102 of 526 (19 %) patients. All 8 patients with para-aortic metastases had also pelvic node metastases. At multivariable analysis, vaginal involvement, type of lymphadenectomy and LN status all significantly negatively affected disease-free survival and overall survival, whereas the number of total LNs removed did not affect survival. LN metastasis and number of LN metastases confer an independent risk for worse survival in patients with CC. Pelvic lymphadenectomy is important for staging and regional disease control when LNs are involved. If a standardized complete lymphadenectomy is performed, the number of LNs is not a significant factor per se.

IF 16.265; International audience; BACKGROUND:The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients.OBJECTIVE:To develop a new model based on real-world patients.DESIGN, SETTING, AND PARTICIPANTS:Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011.INTERVENTION:First-line, platinum-based, combination chemotherapy.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms.RESULTS AND LIMITATIONS:A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p

Background Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. Methods A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H-0 a parts per thousand currency sign 5 %, H-1 a parts per thousand yen 20 %, alpha = 10 % and beta = 20 %). Eligibility included failure of at least one platinum-based regimen. Results From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4 %) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4 %) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1 %), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6 % (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1 %, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9 % mucositis, 36.4 % fatigue, 18.2 % neutropenia (13.6 % febrile neutropenia). There were 2 treatment-related deaths. Conclusions The study did not meet the primary EP, yet sustained disease control was obtained in about 14 % of patients. The incidence of AE and the issue of patient selection are two major concerns.

Background The awareness that adolescents can have cancer is probably insufficient, not only among teenagers and their families, but also among physicians, and adolescent patients are reportedly often referred to qualified cancer institutes after a considerable delay. Procedure A prospective series of 425 patients (28% of them adolescents) with solid tumors was analyzed to investigate the correlation between symptom interval and age, and the different contributions to symptom interval in terms of the time from symptom onset to the first contact with a doctor (patient delay), referral to the oncologist (referral delay), and final diagnosis (oncologist delay). Results The median symptom interval was 47 days for 0 to 14-year-old patients and 137 for those ≥15 years (P

Background. The purpose of our study was to identify the role of work exposure to organic dusts in patients with malignant paranasal sinus tumors. Methods. We analyzed all patients surgically treated for a malignant paranasal sinus tumor at our institution between 1987 and 2006. All patients were specifically asked about their occupational history. The tumor site was classified as maxillary or ethmoid sinus. Adenocarcinomas were divided into intestinal type (ITAC) and non-ITAC. Results. The sample included 345 patients with ethmoid sinus and 301 maxillary sinus. Regarding the ethmoid sinus, we found an exposure to organic dusts in 148 of 153 patients with ITAC, in 3 of 16 patients with non-ITAC adenocarcinoma, and in 10 of 176 patients with other tumors. Regarding the maxillary sinus, we found an exposure in 1 of 20 patients with non-ITAC adenocarcinoma and in 4 of 281 patients with other histologies. Conclusion. Our study demonstrates that only ethmoid ITACs have an indisputable relationship with the exposure to organic dusts. V

426 Background: 6 cycles of platinum-based chemotherapy (CT) are conventionally targeted to treat locally advanced unresectable or metastatic urothelial carcinoma (UC). However, cisplatin is associated with significant cumulative toxicities, which render it challenging to deliver 6 cycles. Since this issue has not been investigated prospectively, we conducted a retrospective analysis. Methods: The Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) database was used to conduct a retrospective analysis. The association of the number of cycles of platinum-based first-line CT with overall survival (OS) was investigated by a Cox regression utilizing multivariate analysis after controlling for previously recognized prognostic factors used in a nomogram ( Eur Urol, 2017). The primary analysis was a comparison of < 6 cycles vs. ≥6 cycles. Six-month landmark analysis was applied throughout, accounting for OS events. Additionally, we excluded patients (pts) receiving < 3 or > 9 cycles to reduce confounding due to early removal for toxicities, progression and patient decision and increased number of cycles due to response and pt-related factors. Results: Of 1020 pts available from RISC, 472 (cisplatin = 338, carboplatin = 134) were evaluable for the landmark analysis with 281 events. A total of 157 pts received 3-5 cycles (median 4) and 315 received 6-9 cycles (median 6). There was no significant difference between 3-5 vs. 6-9 cycles of platinum-based chemotherapy (HR 1.02, 95%CI: 0.77-1.33, p = 0.91). No significant interactions were observed with type of platinum (p = 0.09) and “completed planned CT” (p = 0.56). Comparison of 4 vs. 6 cycles (p = 0.57) and < 6 vs 6 vs 7-9 (p = 0.9) also yielded no significant differences for association with OS. No differential association was observed with survival for 3-5 vs. 6-9 cycles when examining by nomogram-defined risk group tertiles. Limitations of a hypothesis-generating retrospective analysis apply. Conclusions: 4 cycles of platinum based first-line CT appear adequate to treat advanced UC. The omission of excessive cycles will avoid unnecessary toxicities and facilitate better transition to second-line and switch maintenance therapy.

The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and for predictive and prognostic information in lung cancer patients. CD133, a surface glycoprotein linked to organ-specific stem cells, was described as a marker of cancer-initiating cells in different tumor types. Here, we report that a CD133 + , epithelial-specific antigen-positive (CD133 + ESA + ) population is increased in primary nonsmall cell lung cancer (NSCLC) compared with normal lung tissue and has higher tumorigenic potential in SCID mice and expression of genes involved in stemness, adhesion, motility, and drug efflux than the CD133 − counterpart. Cisplatin treatment of lung cancer cells in vitro resulted in enrichment of CD133 + fraction both after acute cytotoxic exposure and in cells with stable cisplatin-resistant phenotype. Subpopulations of CD133 + ABCG2 + and CD133 + CXCR4 + cells were spared by in vivo cisplatin treatment of lung tumor xenografts established from primary tumors. A tendency toward shorter progression-free survival was observed in CD133 + NSCLC patients treated with platinum-containing regimens. Our results indicate that chemoresistant populations with highly tumorigenic and stem-like features are present in lung tumors. The molecular features of these cells may provide the rationale for more specific therapeutic targeting and the definition of predictive factors in clinical management of this lethal disease.

To determine the long-term outcomes of early-stage Merkel cell carcinoma (MCC) patients managed with surgery alone. Ninety-five consecutive patients were reviewed. Patients were treated by wide local excision. Clinically negative regional nodes were either followed up (n = 42) or staged with sentinel lymph node biopsy (n = 21), and clinically positive nodes underwent lymph node dissection (n = 32). Median follow-up was 65 months. A total of 45 (47%) patients relapsed, with 80% of the recurrences occurring within 2 years and 96% within 5 years. The 5-year crude cumulative incidence (CCI) of recurrence and disease-specific survival (DSS) were 52% and 67%, respectively. CCI of local 5-year recurrence was 5% for the study cohort. Patients with MCC in the head and neck region had a 5-year local-recurrence CCI of 19%, and patients with MCC in the extremity and trunk region had a 5-year local-recurrence CCI of 2% (P = 0.007). Comparing patients with ≤ 2 versus > 2 metastatic lymph nodes, the 5-year regional-recurrence CCI was 0% versus 39% (P = 0.004). The 5-year distant-recurrence CCI was higher in clinically node-positive patients compared with node-negative patients (37% versus 12%; P = 0.005). Patients with MCC in the head and neck region experienced no distant recurrences, patients with MCC in the extremity and trunk region had a 5-year distant-recurrence CCI of 22%, and patients with occult primary had a 5-year distant-recurrence CCI of 49% (P = 0.023). The 5-year DSS rate was 80% for pathologically node-negative patients. The prognosis for surgically managed early-stage MCC is variable. Thus multidisciplinary tumor-board consultation is needed to optimize individual patient management.

To assess in vivo volumetric repeatability of an automated software algorithm in pulmonary nodules detected during a lung cancer screening trial.This study was approved by an institutional review board. Written informed consent was obtained from all participants. Data were collected from the Multicentric Italian Lung Detection project, a randomized controlled lung cancer screening trial. The first 1236 consecutive baseline computed tomographic (CT) studies performed at the Istituto Nazionale Tumori of Milan were evaluated. Among the enrolled participants, those who underwent repeat low-dose CT after 3 months and had at least one indeterminate nodule with a volume of more than 60 mm(3) (diameter of 4.8 mm or greater) were considered. Nonsolid, part-solid, and pleural-based nodules were excluded from this study. A descriptive analysis was performed by calculating means and standard deviations of nodule volumes at three assessment times (at baseline and 3 and 12 months later). The volume measurement repeatability was determined by using the approach described by Bland and Altman.One hundred one subjects (70 men, 31 women; mean age, 58 years) with 233 eligible nodules (mean volume, 98.3 mm(3); range, 5-869 mm(3)) were identified. The 95% confidence interval for difference in measured volumes was in the range of +/-27%. About 70% of measurements had a relative difference in nodule volume of less than 10%. No malignant lesions were registered during the follow-up of these subjects.Semiautomatic volumetry is sufficiently accurate and repeatable and may be useful in assisting with lung nodule management in a lung cancer screening program.